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人巨细胞病毒抗原由 HLA-DR+NKG2C+适应性 NK 细胞呈递，特异性激活多功能效应记忆 CD4+T 淋巴细胞。

Human Cytomegalovirus Antigen Presentation by HLA-DR+ NKG2C+ Adaptive NK Cells Specifically Activates Polyfunctional Effector Memory CD4+ T Lymphocytes.

机构信息

Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain.

Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.

出版信息

Front Immunol. 2019 Apr 3;10:687. doi: 10.3389/fimmu.2019.00687. eCollection 2019.

DOI:10.3389/fimmu.2019.00687
PMID:31001281
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6456717/
Abstract

Natural killer (NK) cells play a dual role in the defense against viral pathogens by directly lysing infected cells as well as by regulating anti-viral T cell immunity. Infection by human cytomegalovirus (HCMV) promotes a persistent expansion of NKG2C+ adaptive NK cells which have been shown to display enhanced antibody-dependent responses against infected targets and associated to viral control in transplanted patients. Based on gene expression data showing increased transcription of CIITA and several genes related to the MHC class II pathway in adaptive NK cells, we explored their putative capacity for antigen presentation to CD4+ T cells. Phenotypic analysis confirmed a preferential steady-state expression of HLA-DR by circulating NKG2C+ adaptive NK cells in healthy individuals. Expression of HLA-DR in NKG2C+ adaptive NK cells was variable and unrelated to the expression of activation (i.e., CD69 and CD25) or differentiation (i.e., FcRγ chain, CD57) markers, remaining stable over time at the individual level. Incubation of purified NK cells with HCMV complexed with serum specific antibodies induced an up-regulation of surface HLA-DR concomitant to CD16 loss whereas no changes in CD80/CD86 co-stimulatory ligands were detected. In addition, surface CX3CR1 decreased upon antigen-loading while HLA-DR+ NK cells maintained a CCR7-, CXCR3 homing profile. Remarkably, HCMV-loaded purified NK cells activated autologous CD4+ T cells in an HLA-DR dependent manner. The fraction of T lymphocytes activated by antigen-loaded NK cells was smaller than that stimulated by monocyte-derived dendritic cells, corresponding to CD28-negative effector-memory CD4+ T cells with cytotoxic potential. Antigen presentation by NK cells activated a polyfunctional CD4+ T cell response characterized by degranulation (CD107a) and the secretion of Th1 cytokines (IFNγ and TNFα). Overall, our data discloses the capacity of NKG2C+ adaptive NK cells to process and present HCMV antigens to memory CD4+ cytotoxic T cells, directly regulating their response to the viral infection.

摘要

自然杀伤 (NK) 细胞通过直接裂解感染细胞以及调节抗病毒 T 细胞免疫，在防御病毒病原体方面发挥双重作用。人类巨细胞病毒 (HCMV) 的感染促进了 NKG2C+适应性 NK 细胞的持续扩增，这些细胞已被证明显示出针对感染靶标的增强的抗体依赖性反应，并与移植患者中的病毒控制相关。基于基因表达数据显示适应性 NK 细胞中 CIITA 和几个与 MHC Ⅱ类途径相关的基因的转录增加，我们探讨了它们对 CD4+T 细胞进行抗原呈递的潜在能力。表型分析证实，在健康个体中，循环 NKG2C+适应性 NK 细胞优先稳定表达 HLA-DR。NKG2C+适应性 NK 细胞中 HLA-DR 的表达是可变的，与激活（即 CD69 和 CD25）或分化（即 FcRγ链、CD57）标志物的表达无关，在个体水平上保持稳定。用 HCMV 与血清特异性抗体复合物孵育纯化的 NK 细胞可诱导表面 HLA-DR 的上调，同时伴随着 CD16 的丢失，而没有检测到 CD80/CD86 共刺激配体的变化。此外，抗原加载后表面 CX3CR1 减少，而 HLA-DR+NK 细胞保持 CCR7-、CXCR3 归巢特征。值得注意的是，负载 HCMV 的纯化 NK 细胞以 HLA-DR 依赖的方式激活自体 CD4+T 细胞。被抗原负载的 NK 细胞激活的 T 淋巴细胞的分数小于由单核细胞衍生的树突状细胞刺激的分数，对应于具有细胞毒性潜力的 CD28-阴性效应记忆 CD4+T 细胞。NK 细胞的抗原呈递激活了一种多功能 CD4+T 细胞反应，其特征在于脱颗粒（CD107a）和 Th1 细胞因子（IFNγ和 TNFα）的分泌。总体而言，我们的数据揭示了 NKG2C+适应性 NK 细胞加工和呈递 HCMV 抗原的能力，直接调节它们对病毒感染的反应。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60cc/6456717/cc6fcfa2239b/fimmu-10-00687-g0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60cc/6456717/efd7528d52a2/fimmu-10-00687-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60cc/6456717/6c39708285b3/fimmu-10-00687-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60cc/6456717/cc6fcfa2239b/fimmu-10-00687-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60cc/6456717/1ea007a706de/fimmu-10-00687-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60cc/6456717/c4595603d5a6/fimmu-10-00687-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60cc/6456717/336ce0fc3054/fimmu-10-00687-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60cc/6456717/bd9c1762a8d0/fimmu-10-00687-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60cc/6456717/efd7528d52a2/fimmu-10-00687-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60cc/6456717/6c39708285b3/fimmu-10-00687-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60cc/6456717/cc6fcfa2239b/fimmu-10-00687-g0007.jpg

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本文引用的文献

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HLA-DR NK cells are mostly characterized by less mature phenotype and high functional activity.

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